Best lactamase

A 65-year-old male with a pneumonia has a sputum culture that is positive for a staphylococcal strain that is p-lactamase-positive. Which is the best choice of penicillin therapy in this patient ... 

Hetacillin is a semisynthetic prodrug of ampicillin also inactivated by -lactamases. It is more stable in the gastric acid than ampicillin and amoxicillin and, therefore, is absorbed best. Hetacillin is inactive per se, but after it enters the bloodstream it is metabolized to ampicillin and becomes active. 

Bacterial resistance can occur because of several mechanisms.28,76 Certain bacterial strains may be able to enzymatically destroy the antibacterial drug. The best example is the beta-lactamase enzyme that is found in bacteria that are resistant to beta-lactam drugs (penicillins and cephalosporins).54,86 As previously discussed, bacteria containing this enzyme can destroy certain penicillin and cephalosporin drugs, thus rendering the drug ineffective against these strains. 

As mentioned in the Introduction, bacterial resistance to currently used antibacterial agents poses a major threat to their continued effectiveness [2]. Interestingly, a number of enzymes are involved in the development of antibacterial resistance via several mechanisms. For example, there are enzymes that catalyze the inactivation of antibacterial agents [47], 3-Lactamases are the best-known examples of this class of enzymes and have been studied extensively as targets for new inhibitors that are used in combination with 3-lactams to prevent their inactivation [48], Several [3-lactamase inhibitors have been developed and are used in combination with [3-lactams (e.g., amoxicillin/clavulanic acid, piperacillin/tazo-bactam, and others) [49,50],... 

Clavulanic acid (80), isolated from Strepto-myces clavuligeruSy is similar in structure to the penicillins, except oxygen replaces sulfur in the five-membered ring (123). Clavulanic acid has weak antibacterial activity, but is a potent inhibitor of p-lactamases (124). A mixture of clavulanic acid and the j8-lactamase-sensitive amoxycillin was introduced in 1981 as Augmentin and has proved to be an effective combination to combat jS-lactamase-pro-ducing bacteria (125). In 2001,20 years after its launch, Augmentin is the best-selling antibacterial worldwide. 

Streptomyces clavuligerus. This was essentially devoid of antibacterial activity but was a very effective inhibitor of beta-lactamases produced by a wide variety of bacteria. Some idea of the excitement these results caused can be seen from Beecham s data for the minimum inhibitory dose of ampicillin needed for a typical resistant staphylococcus without clavulanic acid (500 fig ml-1) and with clavulanic acid (less than 0.4 fig ml-1)- Five years later, they were able to demonstrate that the combination of the broad-spectrum penicillin - amoxycillin - with clavulanic acid was very effective in clinical use. This combination was marketed as Augmentin and soon became one of the best-selling drugs in the world market. 

However, none of these drugs has yet attained the star status of ampicillin, amoxycillin or cephalexin. It is also often forgotten that one of the best penicillins is the oldest one of all - penicillin G. It is unstable to acid, destroyed by beta-lactamases, but is nonetheless extremely effective (if given in large enough doses) against such rare conditions (at least in the developed world) as diphtheria, tetanus, anthrax, Lyme disease (a tick-borne disease) and venereal diseases. In addition, it usually produces few side-effects - and is thus a close approximation to a true magic bullet . 

The answer may be in discovering more specific mechanism-based P-lactamase inhibitors. It is curious that the best drugs developed so far are also P-lactam compounds (Fig. 6-14). One very interesting inhibitor is penicillanic acid sulfone (sulbactam, Fig. 6-14). This drug acts as a substrate (becomes hydrolyzed) and as an irreversible inactivator of TEM-type P-lactamase (covalently binding to it via molecular cleavage). 

Supra-additive interactions and potentiation appear to be much less common than antagonism and the simple additive interactions described above. Supra-additive (synergistic) interaction is said to occur if the result of interaction is greater than the sum of the drugs used alone the best example is the therapeutic synergism of certain antibiotic combinations such as sulfonamides and dihydrofolic acid reductase inhibitors such as trimethoprim. Potentiation is said to occur when a drug s effect is increased by another agent that has no such effect. The best example of this type of interaction is the therapeutic interaction of beta-lactamase inhibitors such as clavulanic acid with lactamase-susceptible penicillins. 

Thienamycin, the first of the carbapenems, was isolated from Streptomyces cattleya. Because of its extremely intense and broad-spectrum antimicrobial activity as well as its ability to inactivate (3-lactamases, it combines in one molecule the functional features of the best of the (3-lactam antibiotics as well as the (3-lactamase inhibitors. It differs structurally in several important respects from the penicillins and cephalosporins. The sulfur atom is not part of the 5-membered ring but, rather, has been replaced by a methylene moiety at that position. Carbon is roughly half the molecular size of sulfur. Consequently, the carbapenem ring system is highly strained and very susceptible to reactions cleaving the (3-lactam bond. The sulfur atom is now attached to C-3 as part of a functionalized side chain. 

Amoxycillin 13.9a) and ampicillin 13.9b) resemble penicillin V in being well absorbed orally (amoxycillin, best of all), principally because they are resistant to gastric acidity, and (like penicillin V) they are inactivated by )8-lactamase. 

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